A Case of Autosomal Dominant Osteopetrosis Type 2 with a &lt;i&gt;CLCN7&lt;/i&gt; Gene Mutation

Kang, Su-Tae; Kang, Young Kyung; Lee, Jun Ah; Kim, Dong Ho; Lim, Jung Sub

doi:10.4274/jcrpe.galenos.2019.2018.0229

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…(17) We used a combination of imaging analysis, electrophysiological measurements, and an optical assay to investigate the functional alterations of 13 different ClC-7 protein mutants carrying previously not-tested missense mutations spread throughout the entire gene and identified in patients affected by different forms of osteopetrosis. We also included in this series of mutations the p.Pro249Leu variant that is recurrently identified in ADO2 (18)(19)(20) and has been reported also in two ARO siblings at the compound heterozygous state with the p.Ser744Phe mutation. (14) Our results point to structural-functional correlations that might explain the molecular basis of disease severity.…”

Section: Introductionmentioning

confidence: 99%

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants

Zanni

Palagano

Lagostena

et al. 2020

Journal of Bone and Mineral Research

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ClC‐7 is a chloride‐proton antiporter of the CLC protein family. In complex with its accessory protein Ostm‐1, ClC‐7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC‐7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC‐7 protein, assessed the lysosomal colocalization of ClC‐7 mutants and Ostm1 through confocal microscopy, and performed patch‐clamp recordings on plasma‐membrane‐targeted mutant ClC‐7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC‐7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Section: Introductionmentioning

confidence: 99%

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants

Zanni

Palagano

Lagostena

et al. 2020

Journal of Bone and Mineral Research

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“…Hearing loss may occur in osteopetrosis type 2, however its onset is generally after the second decade of life. Hearing deterioration is usually a secondary nding to osteopetrotic malformation of the temporal bone[21]. Neither our proband nor her father meet the phenotypic criteria of osteopetrosis type 2.…”

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confidence: 73%

Hearing loss as a newly recognized symptom of GSD type I. A clinical report of four unrelated Polish patients.

Iwanicka‐Pronicka¹,

Trubicka²,

Pronicki³

et al. 2020

Preprint

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Background: Glycogen storage disease (GSD) type Ia and Ib is the most severe type of all hepatic GSDs. It presents with serious liver and metabolic complications, as well as in type Ib with severe infections due to neutropenia. So far, the hearing impairment has not been reported in these patients. Hearing status was assessed in a group counting 40 probands with GSDI (20 patients with each subtype). Hearing loss was detected in four patients. They did not pass newborn hearing screening. Due to the development of severe metabolic complications in infancy, audiological diagnosis was postponed until the early school age, when speech and language delay was striking.Hearing tests revealed the bilateral sensorineural hearing impairment with the audiograms presenting ski-slope curves in all patients. Next-generation sequencing (NGS) using gene panel: TruSight OneTM Sequencing Panel Kit (Illumina, San Diego, CA, USA) or whole-exome sequencing (WES) using SureSelect Human All Exon Kit (Agilent, 60mb V6) were performed in order to find possible genetic background of auditory dysfunctions in these patients.Results: Hearing impairment seems to affect about10% GSDI patients. Molecular analysishas revealed the common homozygous pathogenic variant in G6PC in two GSDIa probands. Common pathogenic variant in SLC37A4 gene was identifiedin one GSDIb patient, whereas the second case was found to be a carrier of one common and one rare pathogenic variant in SLC37A4 gene ( in trans ). No change in the genes involved in auditory pathway dysfunction was found, although the patients displayed the same audiological characteristics.Conclusions: Sensorineural hearing lossappears to be a clinical complication of GSDI encountered in approximately one out of ten cases. Carefulmonitoring of auditory functions is recommended among GSDI patients, especially in prelingulal period. Appropriate early detection and intervention (fitting with hearing aids) prevents potential speech and language impairment.

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“…The second osteopetrosis form can be type I or II; both differ in the presentation of clinical features and genetic mutations located in the LRP5 and CLCN7 genes, respectively. Type I derives from enhanced osteoblast activity due to reduced LRP5 affinity for the extracellular antagonists SOST and dikkopf-1 (DKK-1) and consequent increased Wnt canonical signaling [199], while the most common cause of type 2 is the presence of inactivating mutations in the chloride channel 7 (CLCN7) gene, which results in ineffective, osteoclast-mediated bone resorption [200]. The X-linked type of osteopetrosis results from mutations in the IKBKG gene, which encodes for NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, essential for NF-kappa B signaling [201].…”

Section: Osteopetrosismentioning

confidence: 99%

Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases

Otòn-Gonzalez

Mazziotta

Iaquinta

et al. 2022

IJMS

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Bone metabolism consists of a balance between bone formation and bone resorption, which is mediated by osteoblast and osteoclast activity, respectively. In order to ensure bone plasticity, the bone remodeling process needs to function properly. Mesenchymal stem cells differentiate into the osteoblast lineage by activating different signaling pathways, including transforming growth factor β (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1 (Wnt)/β-catenin pathways. Recent data indicate that bone remodeling processes are also epigenetically regulated by DNA methylation, histone post-translational modifications, and non-coding RNA expressions, such as micro-RNAs, long non-coding RNAs, and circular RNAs. Mutations and dysfunctions in pathways regulating the osteoblast differentiation might influence the bone remodeling process, ultimately leading to a large variety of metabolic bone diseases. In this review, we aim to summarize and describe the genetics and epigenetics of the bone remodeling process. Moreover, the current findings behind the genetics of metabolic bone diseases are also reported.

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A Case of Autosomal Dominant Osteopetrosis Type 2 with a <i>CLCN7</i> Gene Mutation

Cited by 5 publications

References 16 publications

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants

Hearing loss as a newly recognized symptom of GSD type I. A clinical report of four unrelated Polish patients.

Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases

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